Discovery could aid fight against cystic fibrosis infection

BOSTON – June 9, 2006 – Harvard Medical School researchers have discovered one
way that a hardy disease-causing bacteria could be surviving in the lungs of
chronically infected cystic fibrosis (CF) patients.

"This work is important because pathogenic bacteria such as Pseudomonas
aeruginosa (PA) use protein secretion systems to cause disease in their
hosts," said Joseph Mougous, lead author of the study published in the June
9 issue of Science. "In the case of Pseudomonas aeruginosa, the host may be
a cancer patient with a weakened immune system, a burn patient, or a person
with cystic fibrosis (CF)."

Pseudomonas aeruginosa (PA), a pathogen that infects more than 80 percent of
cystic fibrosis patients, is a leading cause of these patients' death. PA is
difficult to treat because it is resistant to many drugs.

"Since we know so little about what this bacterium is up to while it's
engaged in these chronic infections, the discovery of this protein secretion
system might lead to finding a new target for treatments," said Mougous, a
research fellow in the Harvard Medical School (HMS) Department of
Microbiology and Molecular Genetics.

Researchers at Argonne National Laboratory (ANL) provided one of the clues
that contributed to the HMS discovery. Working through a number of
pathogenic proteins, ANL protein crystallographer Marianne Cuff saw a
bagel-shaped pore that might be involved in transferring toxins into cells.
She deposited the structure of the protein, called Hcp1, into the Protein
Data Bank, a resource used by biologists worldwide to find information about
the proteins they are studying.

While exploring the Protein Data Bank, Mougous, who was studying PA in the
laboratory of department chair John Mekalanos, recognized that the amino
acid sequence of Hcp1 in PA closely resembled that of Hcp1 in Vibrio
cholerae. The Mekalanos lab had previously discovered that the Hcp1 protein
of V. cholerae is released from the bacterium via a novel secretion
pathway. Because Hcp1 proteins from both pathogens belong to the same
protein family, Mougous wondered whether the Pseudomonas Hcp1 might also be
secreted via this pathway.

The Harvard and Argonne researchers quickly formed a collaboration and
confirmed the hypothesis. They then turned their attention to Hcp1 in cystic
fibrosis patients to gain more insight in the role of Hcp1 during infection.

Working with cystic fibrosis patients at Children's Hospital Boston, the
HMS researchers sought and found Hcp1 in the sputum of patients with P.
aeruginosa. They also found Hcp1 antibodies in the patients' blood – further
evidence that Hcp1 plays a critical role in the infection. The human immune
system creates antibodies to pathogens it is exposed to.

"CF patients are particularly susceptible to PA," Mougous said. "The
bacterium thrives in the excess mucus that accumulates in their lungs. Once
a PA infection in a CF patient's lung has been established, these hardy
bacteria are difficult or impossible to clear, which over many years
eventually results in the death of the patient. Our paper provides evidence
that the protein secretion system we discovered represents at least one way
this bacterium could be promoting its own survival in the lungs of CF
patients."

"This finding provides a possible drug target to fight the infection in
cystic fibrosis patients," added Andzrej Joachimiak, director of Argonne's
Structural Biology Center and of the Midwest Center for Structural Genomics
based at Argonne.

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The research was supported in part by grants from the National Institutes of
Health, the Damon Runyon Cancer Research Foundation, and the U.S. Department
of Energy, Office of Biological and Environmental Research.

The nation's first national laboratory, Argonne National Laboratory conducts
basic and applied scientific research across a wide spectrum of disciplines,
ranging from high-energy physics to climatology and biotechnology. Since
1990, Argonne has worked with more than 600 companies and numerous federal
agencies and other organizations to help advance America's scientific
leadership and prepare the nation for the future. Argonne is managed by the
University of Chicago for the U.S. Department of Energy's Office of Science.